The long-term goal of the proposed work is to use coordinated electrophysiological, computational, and applied mathematical techniques to understand the biophysical underpinnings of synchronous activity in the brain. Because synchronous activity is linked to the behavioral state, seems important for learning and memory, and shows clear abnormalities in clinically important conditions like temporal lobe epilepsy, the results gained from this program should make important contributions to human health. The specific goal of the proposed research is to characterize neurons from brain slices of the hippocampal formation in terms of their abilities to generate coherent population activity via mutual excitation and/or inhibition. To this end, we will adapt and use "mapping" techniques from applied mathematics, along with custom-built "dynamic clamp" technology. Work will focus on the mechanisms underlying two EEG rhythms that appear together during active exploration and learning: the 4-12 Hz theta rhythm and 30-80 Hz gamma rhythm. The effects of known neuromodulatory agents (acetylcholine, norepinephrine, and serotonin), as well as those of a putative neuromodulator (zinc), will be assessed. This appraisal will focus on how the biophysical effects of neuromodulators may alter cellular synchronization properties and hence, change the population driving synchronous activity. Computational and experimental methods will be used to verify the validity of mapping measurements in predicting network behavior. Because the techniques to be used in the proposed work are generally applicable, with clear underlying assumptions, both the results and the newly developed techniques should be broadly pertinent for work in many brain structures that show coherent network activity. Work will be organized around two hypotheses: (A) The biophysical properties of excitatory neurons in excitation-dominated structures support synchronization by mutual excitation; the converse is true for inhibition-dominated structures. (B) Neuromodulators can change the functional architecture of the hippocampal formation by altering cellular properties that determine synchronization behavior.